Antitumor vaccination is quite effective when administered to naive, tumor-free mice resulting in protection from tumor growth upon subsequent challenge. Protection is generally long lasting and tumor specific, indicating the participation of the adaptive immune response. This picture changes radically when vaccines are used for the therapeutic treatment of already established tumor. The same dose of vaccine that is able to effectively establish protective immunity is generally unable to provide therapeutic benefit. The reason for this lack of effectiveness of therapeutic vaccination is thought to stem from the induction of tumor-induced suppressor cells, the generation of regulatory cells, the induction of T-cell anergy or tolerance, or a combination of these mechanisms. Whatever the precise mechanisms of tumor-induced immune suppression, the success of vaccine therapy for cancer treatment will depend on overcoming or neutralizing these tumor-induced suppressive effects.
The heat shock protein (hsp) gp96, localized in the endoplasmic reticulum (ER), is thought to serve as a chaperon for peptides on their way to MHC class I and II molecules. Gp96-chaperoned peptides comprise the entire spectrum of peptides and larger protein fragments generated in cells and transported into the ER. Gp96 obtained from tumor cells and used as a vaccine induces specific tumor immunity, presumably through the transport of tumor-specific peptides to APCs. See J Immunol. 1999 Nov. 15; 163(10):5178-82.
The invention described in this application provides an antitumor composition. Heat shock protein glycoprotein (gp) 96-associated peptides are cross-presented to CD8 cells by dendritic cells. A vaccination system was developed suitable for antitumor therapy. See J Immunother. 2008 May; 31(4):394-401, and references cited therein. Transfecting a gp96-immunoglobulin (Ig) G1-Fc fusion protein into tumor cells results in the secretion of gp96-Ig in complex with chaperoned tumor peptides. Parenteral administration of gp96-Ig secreting tumors triggers robust, antigen specific CD8 cytotoxic T lymphocyte expansion combined with activation of the innate immune system. Tumor-secreted gp96 causes the recruitment of dendritic cells (DCs) and natural killer (NK) cells to the site of gp96 secretion and mediates DC activation via binding to CD91 and Toll-like receptor-2 and Toll-like receptor-4. The endocytic uptake of gp96 and its chaperoned peptides triggers peptide cross presentation via major histocompatibility complex (MHC) class I and strong, cognate CD8 activation independent of CD4 cells. In this model system, CD8 CTL expansion can be precisely quantitated within 4 to 5 days of vaccination by the use of adoptively transferred, T-cell receptor (TCR) transgenic, green fluorescent protein (GFP)-marked CD8 T cells.